Regulation of Estrogen Receptor α by the SET7 Lysine Methyltransferase

Abstract

Estrogen receptor alpha (ER) is a ligand-dependent transcription factor. Upon binding estrogen, ER recruits coactivator complexes with histone acetyltransferase or methyltransferase activities to activate downstream target genes. In addition to histones, coactivators can modify ER itself and other proteins in the transactivation complex. Here, we show that ER is directly methylated at lysine 302 (K302) by the SET7 methyltransferase. SET7-mediated methylation stabilizes ER and is necessary for the efficient recruitment of ER to its target genes and for their transactivation. The SET7-ER complex structure reveals the molecular basis for ER peptide recognition and predicts that modifications or mutations of nearby residues would affect K302 methylation. Indeed, a breast cancer-associated mutation at K303 (K303R) alters methylation at K302 in vitro and in vivo. These findings raise the possibility that generation, recognition, and removal of modifications within the ER hinge region generate "ER modification cassettes" that yield distinct patterns for signaling downstream events.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…These studies suggest that the role of SET7 methylation in transcriptional activation reaches beyond the modification of histones. Using an in vitro methylation assay of peptide substrates (ERα, androgen receptor (AR), glucocorticoid receptor (GR) and mutant ERα), and recombinant purified HMTases, the methylation of lysine in the ERα hinge region was found to be specifically targeted by SET7 [142]. Through mass spectrometric analysis, K302 was identified as the only site of methylation by SET7 within the ERα hinge region in vitro (Fig.…”

“…The antibody's specificity and sensitivity for this methylated residue were convincingly demonstrated by dot-blot analysis. SET7-mediated methylation stabilizes ERα and is necessary for the efficient recruitment of ERα to its target genes and for their transactivation [142].…”

Les modifications post-traductionnelles orchestrent l’action du récepteur des œstrogènes εRα dans les tumeurs mammaires

“…Par exemple, la sérine 236, phosphorylée par la PKA, joue un rôle dans la Très récemment, il a été montré que la méthyltransfé-rase SET7 méthyle la lysine 302 de la région charnière et stabilise le récepteur. Cette méthylation est néces-saire au recrutement de ER au niveau des promoteurs des gènes cibles et à l'activation de la réponse transcriptionnelle induite par les oestrogènes [17]. L'ensemble de ces modifications étant réversible et très dynamique, celles-ci peuvent être un moyen de régu-ler l'assemblage et le désassemblage des complexes transcriptionnels liés à ER.…”

“…SET7 sur la lysine 302 [17]. Sachant que la méthyla-tion sur lysine stabilise ER, il semble donc probable que l'acétylation de la lysine 303 empêche la méthyla-tion de ER sur la lysine 302, déstabilisant ainsi ER, ce qui participerait à l'effet négatif de l'acétylation de la lysine 303 sur la transcription.…”

Lysine methylation regulates the pRb tumour suppressor protein

“…A family of lysine methyltransferases has been described, typically characterized by a conserved Set domain (Zhang and Reinberg, 2001;Xiao et al, 2003). In addition to histones, the mono-methyltrans-ferase Set7/9 has been shown to methylate lysine residues in non-histone proteins, including proteins involved with transcriptional control TAF10, p53 and the oestrogen receptor (Chuikov et al, 2004;Kouskouti et al, 2004;Subramanian et al, 2008).…”